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For six years now, life has been really good for James. He has a great job as the creative director of an advertising firm in New York City. He enjoys spending time with his wife and kids.

And it has all been possible, he says, because for the past six years he has been taking a drug called ketamine.

Before ketamine, James was unable to work or focus his thoughts. His mind was filled with violent images. And his mood could go from ebullient to dark in a matter of minutes.

Ketamine “helped me get my life back,” says James, who asked that we not use his last name to protect his career.

Ketamine was developed as a human and animal anesthetic in the 1960s. And almost from the time it reached the market it has also been used as a mind-bending party drug.

But ketamine’s story took a surprising turn in 2006, when researchers at the National Institutes of Health showed that an intravenous dose could relieve severe depression in a matter of hours. Since then, doctors have prescribed ketamine “off label” to thousands of depressed patients who don’t respond to other drugs.

And pharmaceutical companies are testing several new ketamine-related drugs to treat depression. Johnson & Johnson expects to seek approval for its nasal spray esketamine later this year, though the approval would be limited to use in a clinical setting.

Meanwhile, doctors have begun trying ketamine on patients with a wide range of psychiatric disorders other than depression. And there is now growing evidence it can help people with anxiety, bipolar disorder, post-traumatic stress disorder, and perhaps even obsessive-compulsive disorder.

“I think it’s actually one of the biggest advances in psychiatry in a very long time,” says Dr. Martin Teicher, an associate professor of psychiatry at Harvard Medical School and director of the Developmental Biopsychiatry Research Program at McLean Hospital.

Ketamine may also offer new hope for people like James who have symptoms of several different psychiatric disorders.

James had a happy childhood, he says. But his thoughts were out of control. “I always felt like I was crossing a freeway and my thoughts were just racing past me,” he says.

He spent much of his childhood terrified of “an unknown, an ambiguous force out there.” The fear was “overwhelming,” he says. “I literally slept with the cover over my head with just room to breathe through my mouth until I went to college.”

And there was something else about James: his body temperature.

“I overheated constantly,” he says. “I would wear shorts all year long. In my 20s in my apartment I would sleep with the windows open in the middle of the winter.”

In his late 20s, James saw a doctor who told him he had attention deficit hyperactivity disorder. So he started taking stimulants.

At first, the pills helped him focus. Then they didn’t, no matter how many he took.

He’d done well as an idea guy in the advertising industry. But now James was trying to work at home, and it wasn’t going well.

“ADHD pills will make you interested in anything,” he says. “So I was putting the desk together and taking the desk apart. I was putting a laptop stand together and taking it apart. I was going in a massive downward spiral.”

James had always suffered from mood swings. But now they were rapid and extreme. And he couldn’t stop thinking about gruesome scenarios, like a murderer coming for his family.

“My wife took a summer off to be with me because she was scared of what was going to happen to me,” he says. “She would go to work for a few hours, then rush home. There would be times I’d call her just screaming, ‘Please come home. I can’t get through another minute.’ ”

Eventually, James found his way to Dr. Demitri Papolos, an associate professor of clinical psychiatry at Albert Einstein College of Medicine.

“He was like a whirling dervish when he came into my office,” Papolos says. “He was extremely fearful and scanning the environment all the time and he overheated at the drop of a hat.”

Papolos diagnosed James with a variant of bipolar disorder he calls the “fear of harm phenotype.” It typically appears in childhood and often doesn’t respond to traditional psychiatric drugs.

But Papolos has found that the condition does respond to ketamine. “It’s been transformational,” he says.

In January, Papolos published a study of 45 children with the problem. They inhaled a nasal mist containing ketamine about twice a week. Nearly all got dramatically better.

Scientists still aren’t sure why ketamine works, but there’s evidence that it encourages the brain to rewire, to alter the connections between cells. That process has been linked to recovery from depression. And it may also explain why ketamine helps people who have symptoms associated with several different psychiatric disorders.

One of those effects involves a part of the brain involved in temperature regulation. And that could explain why patients like James usually stop overheating once they are taking ketamine.

James started taking a ketamine nasal spray every other day. He says his response was dramatic.

“One day I turn to my wife and I’m like, ‘I feel calm today. I don’t know if it’s the sun coming in, I don’t know if it’s just the way we’re sitting here, but I feel like I could go and sit at the computer and work.’ ”

The next day, James did sit down at his computer. A month later, he was back at work.

Like this:

SEAN SPENCER WAS ready to give up. For two years, since suffering a major panic attack, the entrepreneur had been living under a cloud of depression. Nothing seemed to make it better. He took traditional antidepressants, but they made him “want to die.” Meditation gave him a fleeting sense of relief, but it wasn’t enough to get him through the day. Out of desperation, he finally traveled to a clinic to try a controversial new therapy: ketamine IV infusions.

Ketamine, first synthesized in 1962, has long been used as a clinical anesthetic and animal tranquilizer—but it’s also known as the hallucinogenic club drug Special K. Spencer remembers being afraid of having a bad trip. “The first time I was in this chair I was pretty nervous,” he says. “I certainly didn’t know what to expect.” As a low dosage of ketamine entered his bloodstream through the IV, he reclined back in the leather chair and his anxiety began to fade away.

When used correctly, ketamine is a cheap and effective pain killer. When abused, it can send users into what’s known as a K-hole, an out-of-body experience that’s been described as a kind of mental paralysis. But growing evidence shows that low doses given intravenously may be life-changing for patients with treatment-resistant depression. And dozens of clinics across the nation have embraced this new strategy in the fight against depression, as also reported in Los Angeles Magazine.

At the Ketamine Clinics of Los Angeles, anesthesiologist Steven Mandel has given more than 4,000 infusions over the past four years. “The other antidepressants take weeks to months to have an effect. Ketamine kicks in within hours,” he says. “It works on people that nothing else has worked on.” According to the National Institutes of Health, up to a third of those suffering from depression don’t respond to prescription antidepressants like selective serotonin reuptake inhibitors—and people like Spencer, desperate for new options, are seeking out ketamine clinics.

The infusions last 50 to 55 minutes and cause mild hallucinations. But it doesn’t come close to the intensity of the dreaded K-hole. “I don’t think anybody should be afraid of it, Spencer says. “You’re not getting handed pills at a club by somebody. You’re going to a professional and you’re in a space that’s safe.” Mandel monitors his patients throughout the procedure and adjusts the dosage accordingly. “After about five minutes you’re blasting off,” Spencer says. “When you get to the deepest part of it you feel ultimate peace.”

While Spencer says the treatment has been life-changing for him, it doesn’t come cheap. At the Ketamine Clinics of Los Angeles, infusions cost anywhere from $600 to $750 a pop. That’s unaffordable for many patients—so Mandel’s clinic mostly ends up serving professionals from the Los Angeles tech community known as “Silicon Beach.”

Spencer is the cofounder of a successful startup and he’s well aware of his advantages. “Objectively I know that I have a lot to be grateful for, and it seems like somebody looking at my life from the outside would think, ‘What does that guy have to be depressed about?’ but it doesn’t work like that,” Spencer says. “You have to look at your brain almost like an operating system, and if that system crashes it doesn’t matter if you have all the comforts of life. You’re still miserable.”

He isn’t alone. According to a 2015 study, entrepreneurs are twice as likely to suffer from depression. That may be due to a combination of work-related stress and higher rates of diagnosis thanks to better health care access. And it’s often a taboo subject in competitive industries like tech. “If you’re admitting to maybe having anxiety or being depressed, you’re giving the impression that you’re weak,” Spencer says.

Doctors still don’t fully understand how depression works, which makes studying and developing new treatments all the more challenging. “We don’t know how any of these meds work on the brain,” says Mandel. “We know about as much about ketamine as we do about any of the others. We do know that ketamine tends to cause new growth in the brain.”While the medical community is still waiting on the results from the first large scale clinical trials, proponents like Mandel are already convinced that the ketamine therapy works on patients with severe depression and suicidality. Out of more than 600 patients, he says he’s seen an improvement in 83 percent of them. And a growing number of studies support claims that ketamine is an effective antidepressant.

But many doctors don’t support the treatment. “The main critique is that it’s been rolled out into clinical usage too soon. There’s so much about the drug that we don’t know in terms of how to use it, who responds to it, what the long term consequences of taking the drug might be,” says Victor Reus, a practicing psychiatrist and professor at the UCSF School of Medicine. “We need to have more, larger, well controlled trials using this drug. We need to follow people over time.”

And there are other concerns. While Ketamine as an anesthetic is FDA approved, using it for depression is not. That means many insurance carriers don’t cover it, limiting its reach to lower income communities. Then there’s the risk of long term dependency on a treatment that some worry may prove to be addictive. “Ketamine is theoretically addictive based on what we see in individuals who are using ketamine recreationally and in street usage,” Reus says.

But talk to patients like Sean Spencer and the concerns melt away. “I hope in the future that it’s more accessible,” Spencer says. “I know people who have been on the brink of suicide and done it and it’s 180 changed their lives.”

Like this:

Ketamine is a powerful sedative that gained a lot of notoriety in the ‘90s for its use as a rave drug. But in the last couple of years, it’s gone legit. Doctors have recognized its potential as an anti-depressant that can be used when other therapies don’t work and have even begun to explore its use for treating migraines.

Adding to the medical literature on ketamine’s use as a depression treatment, a paper published in The American Journal of Psychiatry in early December shows that clinically depressed patients treated with ketamine had a major reduction in suicidal thoughts compared to a control group that didn’t received the drug.

Just as importantly, the patients experienced a measurable reduction in suicidal thoughts, measured by self-reporting, in just 24 hours. This suggests that ketamine is a promising addition to traditional anti-depressants, which can take weeks to start working — if they work at all.

Ketamine used illicitly is usually dried on glass and scraped up, but in a clinical setting it’s administered by an intravenous infusion.

Depression is a challenging condition to treat because psychiatrists can’t necessarily agree on its chemical causes. So, when a treatment shows benefits as rapid and positive as ketamine, they take notice. As the United States suicide rateincreased 24 percent between 1999 and 2014, doctors are keen on finding solutions.

In this trial, 80 patients with major depressive disorder — 43 of whom were already taking an antidepressant of some sort — had checked into the New York State Psychiatric Institute for the study. The experimental group received an intravenous ketamine infusion, while the control group received an infusion of the anesthetic midazolam, which is better known by its brand name, Versed. Just one day after treatment, 55 percent of the ketamine group reported a 50 percent or greater reduction in suicidal ideation, compared to 30 percent of the control group. They also experienced a greater improvement in mood compared to the control group. These effects lasted for six weeks.

“It does suggest ketamine treatment can help someone who’s in a really serious suicidal state get out of that quickly,” first author Michael Grunebaum, an associate professor of psychiatry at Columbia University Medical Center, told Gizmodo. “Certainly, it would be a relatively simple treatment to provide at hospitals.”

Ketamine still isn’t approved by the U.S. Food and Drug Administration for treating depression, but continued positive outcomes, like those found in this study, should help change that.

Like this:

SEAN SPENCER WAS ready to give up. For two years, since suffering a major panic attack, the entrepreneur had been living under a cloud of depression. Nothing seemed to make it better. He took traditional antidepressants, but they made him “want to die.” Meditation gave him a fleeting sense of relief, but it wasn’t enough to get him through the day. Out of desperation, he finally traveled to a clinic to try a controversial new therapy: ketamine IV infusions.

Ketamine, first synthesized in 1962, has long been used as a clinical anesthetic and animal tranquilizer—but it’s also known as the hallucinogenic club drug Special K. Spencer remembers being afraid of having a bad trip. “The first time I was in this chair I was pretty nervous,” he says. “I certainly didn’t know what to expect.” As a low dosage of ketamine entered his bloodstream through the IV, he reclined back in the leather chair and his anxiety began to fade away.

When used correctly, ketamine is a cheap and effective pain killer. When abused, it can send users into what’s known as a K-hole, an out-of-body experience that’s been described as a kind of mental paralysis. But growing evidence shows that low doses given intravenously may be life-changing for patients with treatment-resistant depression. And dozens of clinics across the nation have embraced this new strategy in the fight against depression, as also reported in Los Angeles Magazine.

At the Ketamine Clinics of Los Angeles, anesthesiologist Steven Mandel has given more than 4,000 infusions over the past four years. “The other antidepressants take weeks to months to have an effect. Ketamine kicks in within hours,” he says. “It works on people that nothing else has worked on.” According to the National Institutes of Health, up to a third of those suffering from depression don’t respond to prescription antidepressants like selective serotonin reuptake inhibitors—and people like Spencer, desperate for new options, are seeking out ketamine clinics.

The infusions last 50 to 55 minutes and cause mild hallucinations. But it doesn’t come close to the intensity of the dreaded K-hole. “I don’t think anybody should be afraid of it, Spencer says. “You’re not getting handed pills at a club by somebody. You’re going to a professional and you’re in a space that’s safe.” Mandel monitors his patients throughout the procedure and adjusts the dosage accordingly. “After about five minutes you’re blasting off,” Spencer says. “When you get to the deepest part of it you feel ultimate peace.”

While Spencer says the treatment has been life-changing for him, it doesn’t come cheap. At the Ketamine Clinics of Los Angeles, infusions cost anywhere from $600 to $750 a pop. That’s unaffordable for many patients—so Mandel’s clinic mostly ends up serving professionals from the Los Angeles tech community known as “Silicon Beach.”

Spencer is the cofounder of a successful startup and he’s well aware of his advantages. “Objectively I know that I have a lot to be grateful for, and it seems like somebody looking at my life from the outside would think, ‘What does that guy have to be depressed about?’ but it doesn’t work like that,” Spencer says. “You have to look at your brain almost like an operating system, and if that system crashes it doesn’t matter if you have all the comforts of life. You’re still miserable.”

He isn’t alone. According to a 2015 study, entrepreneurs are twice as likely to suffer from depression. That may be due to a combination of work-related stress and higher rates of diagnosis thanks to better health care access. And it’s often a taboo subject in competitive industries like tech. “If you’re admitting to maybe having anxiety or being depressed, you’re giving the impression that you’re weak,” Spencer says.

Doctors still don’t fully understand how depression works, which makes studying and developing new treatments all the more challenging. “We don’t know how any of these meds work on the brain,” says Mandel. “We know about as much about ketamine as we do about any of the others. We do know that ketamine tends to cause new growth in the brain.”

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While the medical community is still waiting on the results from the first large scale clinical trials, proponents like Mandel are already convinced that the ketamine therapy works on patients with severe depression and suicidality. Out of more than 600 patients, he says he’s seen an improvement in 83 percent of them. And a growing number of studies support claims that ketamine is an effective antidepressant.

But many doctors don’t support the treatment. “The main critique is that it’s been rolled out into clinical usage too soon. There’s so much about the drug that we don’t know in terms of how to use it, who responds to it, what the long term consequences of taking the drug might be,” says Victor Reus, a practicing psychiatrist and professor at the UCSF School of Medicine. “We need to have more, larger, well controlled trials using this drug. We need to follow people over time.”

And there are other concerns. While Ketamine as an anesthetic is FDA approved, using it for depression is not. That means many insurance carriers don’t cover it, limiting its reach to lower income communities. Then there’s the risk of long term dependency on a treatment that some worry may prove to be addictive. “Ketamine is theoretically addictive based on what we see in individuals who are using ketamine recreationally and in street usage,” Reus says.

But talk to patients like Sean Spencer and the concerns melt away. “I hope in the future that it’s more accessible,” Spencer says. “I know people who have been on the brink of suicide and done it and it’s 180 changed their lives.”

Like this:

Study participants bravely took LSD and ketamine in the name of science.

Scientists have found the first evidence of a higher state of consciousness and, unsurprisingly, it was in the brains of people who were tripping.

For the study, published in the journal Scientific Reports, researchers at the University of Sussex reanalyzed brain scans of healthy volunteers who took one of three psychedelic drugs: ketamine, LSD, or psilocybin, the active compound in shrooms, or a placebo. (A team from Imperial College London and the University of Cardiff collected the initial data.)

The scans looked for tiny magnetic fields produced in subjects’ brains to measure neural signal diversity, or the complexity of brain activity. The diversity of brain signals is a mathematical index for the level of consciousness; people who are awake have more diverse brain signal activity than people who are asleep, under anesthesia, or in a vegetative state, for example.

The researchers found that all three drugs produced higher levels of brain signal diversity than the baseline “awake” state observed in people in the placebo group. They found similar changes in signal diversity even though the drugs are very different, pharmacologically, and noted that people who reported more intense experiences had more brain signal changes.

This doesn’t necessarily mean that people who got the drugs were thinking more philosophically, or that this is a “better” brain state; just that their brains operated at a different, higher level than normal.

“During the psychedelic state, the electrical activity of the brain is less predictable and less ‘integrated’ than during normal conscious wakefulness—as measured by ‘global signal diversity,'” Anil Seth, co-director of the Sackler Centre for Consciousness Science at the University of Sussex, said in a release. “Since this measure has already shown its value as a measure of ‘conscious level,’ we can say that the psychedelic state appears as a higher ‘level’ of consciousness than normal—but only with respect to this specific mathematical measure.”

The team wants to confirm its results with more sophisticated methods but they’re cautiously excited, especially because this study could help inform discussions about medically supervised use of the drugs.

Robin Cahart-Harris, head of psychedelic research at Imperial College London, one of the schools that conducted the original experiment, saidthat “the present study’s findings help us understand what happens in people’s brains when they experience an expansion of their consciousness under psychedelics. People often say they experience insight under these drugs—and when this occurs in a therapeutic context, it can predict positive outcomes. The present findings may help us understand how this can happen.”

And in what the release notes is “a striking coincidence,” this study was released exactly 74 years after Albert Hoffman, who synthesized LSD in 1938, conducted his first self-experiment with the drug. April 19, 1943, is known as “bicycle day” for Hoffman’s bike ride home after that fateful acid trip.

The powerful tranquiliser ketamine should be kept off a worldwide illegal drugs list despite it being abused by clubbers, doctors are arguing.

They say it should always be treated as a medicine and not be placed under United Nations illicit drug restrictions The World Federation of Societies of Anaesthesiologists is calling for global support for its initiative to protect ketamine’s status as an essential medicine for anaesthesia and pain relief.

China and other countries which have a problem with ketamine abuse want the drug included on the UN schedule for controlled drugs.

Dr Jannicke Mellin-Olsen, newly-elected WFSA President, spoke out at the group’s World Congress in Hong Kong.

She said: “Ketamine is an essential anaesthetic and painkiller, especially in countries with limited options and poor storage facilities in their hospitals.”

Ketamine is used as the sole available safe anaesthetic in many parts of the world and is widely used in adults and children alike.

Experts say it is also easily transported in situations such as disasters, in which vital lifesaving surgery can take place at the scene of the disaster, even outside the hospital.

Ketamine is an essential anaesthetic and painkiller, especially in countries with limited options and poor storage facilities in their hospitals.Dr Jannicke Mellin-Olsen

But China and some other Asian countries, including Thailand, have problems with ketamine abuse. They want access to be restricted in the same way that morphine is a scheduled or controlled substance.

The UN’s Commission on Narcotic Drugs (CND) has so far not submitted to their demands. The World Health Organisation (WHO) has reviewed ketamine use several times since 2004 when the International Narcotics Control Board (INCB) first noted illicit use was a problem and encouraged countries to place the drug under controls.

On each occasion, WHO has repeatedly warned that placing ketamine under international control would devastate access to safe surgery for billions.

Dr Mellin-Olsen, who is based at Baerum Hospital in Norway, added: “Of course there are legitimate concerns about ketamine abuse, and these shouldn’t be discounted.

“However, it also needs to be recognised that there is little to no evidence that abuse occurs in countries where it is the most essential anaesthetic.

“The international drug control system has caused immense harm to access to medicines, and the system is still, today, out of balance.”

WFSA has launched a “Ketamine is Medicine” campaign against the drug being subjected to international controls.

Dr Mellin-Olsen added: “We call on the UN’s Expert Committee on Drug Dependence not to recommend any further restrictions on ketamine pending the collection of more reliable and complete data on the effects that this might have on the availability of this essential anaesthetic drug, and on patient outcomes around the world.”

Associate Professor Philip Peyton, of Austin Hospital and the University of Melbourne in Australia, told the Congress: “Ketamine’s unique safety profile and effectiveness make it irreplaceable in anaesthetic practice.

“However, concerns about ketamine’s recreational abuse have prompted international calls for its withdrawal.

“This comes at an unfortunate time, as there is increasing interest in ketamine’s other potential therapeutic effects on chronic pain and postoperative delirium, which are now recognised as common and serious postoperative complications, as well as a possible emerging role in management of severe treatment-resistant depression.

“Its unique value in the management of severe pain after surgery or trauma is now widely appreciated.” He added:

“Much research still needs to be done to properly define the value of ketamine and its importance in clinical practice before any decisions about the future availability are made.”

Treating an addiction to a mind-altering substance with another mind-altering substance might seem counterintuitive, but more and more, researchers are finding ways that psychedelic drugs like psilocybin mushrooms and party drugs like ketamine could actually help people get over alcohol and drug addictions.

Most recently, researchers published a study in the Nature journal Neuropsychopharmacology that they say offers very preliminary evidence that ketamine might be worth exploring as a way to help people with alcohol abuse disorders get over the depression and anxiety that they frequently feel after giving up booze.

That particular study was based on mice, which means that on its own, it would hardly be worth mentioning — alcoholic mice being very different from humans with drinking problems. But that’s far from the only research showing that ketamine can help with depression or that psychedelics can help addicts.

For the study in Neuropsychopharmacology, researchers showed that alcohol dependent mice display anxiety and depressed behavior after abstaining from drinking. Then, they were able to show that ketamine was able to reverse those effects, causing the mice to behave like mice who hadn’t been consuming alcohol in the first place.

These findings fit into a growing body of research that shows ketamine can reverse depression in people in powerful ways.

We might think of ketamine as a quasi-psychedelic party drug (or an animal tranquilizer), but researchers have been investigating its therapeutic properties for the past 10 years.

For many, the disassociative anesthetic drug can function as a powerful antidepressant, able to reverse even major depression in just a few hours.

Ketamine, in the days it was used as an animal tranquilizer.

“This is the next big thing in psychiatry,” San Francisco psychiatrist L. Alison McInnes recently told The Washington Post.

Right now, medical experts are trying to find ways to make that anti-depressant effect last as long as possible — for some patients it lasts longer than others, but rarely longer than a few weeks. And some experts argue that there’s there’s not enough good evidence that ketamine really relieves depression to promote using it at all so far. It’s certainly not yet widely available or affordable.

The science is far from settled. Still, other researchers are investigating ways that ketamine may actually have a protective effect that preventscertain patients from becoming depressed in the first place.

Of course, dealing with the depression that follows addiction isn’t the same thing as treating that abuse disorder in the first place.

Researchers are turning to other (still illegal) controlled substances to see whether some might work for treating addictive behavior.

Other researchers have shown (in small studies, so far) that psilocybin mushrooms, also known as magic mushrooms, can have a significant effect on problem drinkers, increasing abstinence rates and decreasing cravings for alcohol.

Taking psychedelic drugs in a clinical setting is far different from self-experimentation, and there’s still a lot of research that’s needed before these things find their way into common clinical use — something that’s currently illegal.

But as this growing body of research shows, it seems there may be far more to many of these substances than their reputations so far suggest.

Like this:

The experimental drug esketamine (also known as ketamine) has been placed on the fast track for U.S. Food and Drug Administration approval for treating major depression, according to Janssen Pharmaceutical.

Ketamine — perhaps best known as a street drug — is listed by the World Health Organization as an important anesthetic and has been used off-label for pain, anxiety, depression and post-traumatic stress disorder, CNN reported.

In 1970, the drug received FDA approval for use in people and was used on American soldiers in Vietnam as an analgesic and sedative. However, doctors became reluctant to use it because it caused minor hallucinogenic side effects.

If the new use gets the go-ahead from the FDA, it would be the first new treatment for major depression approved in about half a century, according to CNN.

A breakdown product of the drug reduces signs of depression in mice without side effects .

The popular club drug ketamine—or ‘Special K’—is also a fast-acting antidepressant, but how it works has eluded scientists. Now a team reports in Nature that the mood-lifting effect may not be caused by the drug itself, but by one of the products formed when the body breaks the drug down into smaller molecules.

“The whole field has become interested in ketamine,” says Todd Gould, a neuroscientist at the University of Maryland School of Medicine in Baltimore who led the study. “It does something different in patients than any other drug we have available.”

But ketamine has its drawbacks: some people are turned off by the high—a feeling of dissociation and sensory distortion that lasts for about an hour. For others, the effect is an incentive to misuse the drug. Ketamine is not yet approved to treat depression in the United States, but ketamine clinics have sprung up around the country to administer it off-label.

Researchers have been racing to find other drugs that produce ketamine’s antidepressant effects without the high, but have been struggling to do so without a clear idea of how ketamine fights depression. Many of those efforts have focused on drugs that target cellular receptors in the brain called NMDA receptors. These were thought to be ketamine’s target, but clinical trials of other drugs that target them have largely yielded disappointing effects on depression, says Gould.

METABOLIC LIFT

“Ketamine probably represents a new chapter in the treatment of depression,” says Roberto Malinow, a neuroscientist at the University of California, San Diego. “But there have been some big questions regarding how it works.”

Gould teamed up with clinicians, analytical chemists, and neurophysiologists to fill in the gaps in understanding. Gould and his colleagues used a battery of behavioural tests in mice to show that one of ketamine’s breakdown products—a compound called (2R,6R)-hydroxynorketamine—is responsible for much of the drug’s antidepressant effects.

And to Gould’s surprise, the metabolite did not cause side effects in the mice even at doses nearly 40 times higher than the antidepressant dose of ketamine. The mice also did not tend to press a lever to receive the metabolite when given the option to self-administer it.

The researchers plan to gather the safety data needed to take the metabolite into clinical testing in humans, a process that Gould cautions could still take years.

But Husseini Manji, head of neuroscience research and development at Janssen Pharmaceutical Companies in Titusville, New Jersey, cautions against assuming that results in mice will bear out in humans. “We have to keep reminding ourselves that clinical data trump rodent data,” he says. Janssen has developed a specific form of ketamine, called esketamine, that it is testing in five large clinical trials.

RECEPTIVE TARGETS

Gould’s study in mice held another surprise: the metabolite that is active in mice did not act through NMDA receptors. The group did not find its direct target, but did find evidence that it stimulates another set of receptors called AMPA receptors. If the same result holds true in humans, it could provide an explanation for why drugs that target NMDA receptors have failed to capture ketamine’s full effects. “This could shake the windows and rattle the walls of those companies that have been putting a lot of money into this research,” says Malinow.

Manji, who describes the study as elegant, is not ready to give up on NMDA receptors until the results have been borne out in human studies. But he is among the researchers who believe that AMPA receptors may be important as well. Janssen and others have been pursing those receptors and proteins associated with them as potential drug targets. “This paper gives us even more impetus to go after them,” says Manji.

UNSW researchers say studies show ketamine can reduce the symptoms of depression within hours.

A $2 million grant from the Federal Government has been awarded for research into use of the drug ketamine as a new treatment option for major depression, the largest clinical trial of its kind in Australia.

According to the Black Dog Institute, an organisation that focuses on mood disorders, about one third of people suffering from major depression do not respond to traditional anti-depressant medication.

“We need to properly test if we can use ketamine as a treatment over a whole course of multiple doses”, said Professor Colleen Loo, who is leading the study from the University of New South Wales and the Black Dog Institute.

“Is it effective and is it safe? We don’t actually have that data [and] this trial will answer that question.”

Ketamine is used in Australia as an anaesthetic and pain killer and can only be prescribed by a doctor. The Therapeutic Goods Administration has not approved its use as a depression treatment.

The drug is also used recreationally and can lead to out-of-body experiences and a sense of intoxication.

“I think controversy surrounding ketamine [is that] it is used as a drug of abuse and so there are concerns, but if used in a carefully, controlled medical context, then that hasn’t been shown to be a problem,” Professor Loo told the ABC.

PHOTO The study is being led by Professor Colleen Loo.

“It’s one of these fields where the clinical application has run ahead of proper research testing,” Professor Loo said.

“Clinics have run ahead and actually started to treat people and to run it as a business, so that’s why this trial is so critical to do now and as quickly as we can.”

Trial involving 200 patients due to start April 2016

The trial is expected to start in April 2016, and will enrol 200 patients who have not responded to existing medication. The trial will compare the effects of ketamine against an active placebo treatment over the course of four weeks.

According to the university, previous studies have shown a single dose of the drug can reduce the symptoms of depression within hours, even in treatment-resistant patients.

“If you give a single treatment, the studies show that you get an amazing anti-depressant response that lasts at least a few days,” Professor Loo said.

“But what no study has shown is how can you use it as a clinically useful treatment to get a lasting response.”

The grant is a part of a $630 million investment from the Federal Government for more than 800 health and prevention of disease projects around the country.